Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia

Mato, AR; Woyach, JA; Brown, JR; Ghia, P; Patel, K; Eyre, TA; Munir, T; Lech-Maranda, E; Lamanna, N; Tam, CS; Shah, NN; Coombs, CC; Ujjani, CS; Fakhri, B; Cheah, CY; Patel, MR; Alencar, AJ; Cohen, JB; Gerson, JN; Flinn, IW; Ma, S; Jagadeesh, D; Rhodes, JM; Hernandez-Ilizaliturri, F; Zinzani, PL; Seymour, JF; Balbas, M; Nair, B; Abada, P; Wang, C; Ruppert, AS; Wang, D; Tsai, DE; Wierda, WG; Jurczak, W

Author(s): Mato, AR; Woyach, JA; Brown, JR; Ghia, P; Patel, K; Eyre, TA; Munir, T; Lech-Maranda, E; Lamanna, N; Tam, CS; Shah, NN; Coombs, CC; Ujjani, CS; Fakhri, B; Cheah, CY; Patel, MR; Alencar, AJ; Cohen, JB; Gerson, JN; Flinn, IW; Ma, S; Jagadeesh, D; Rhodes, JM; Hernandez-Ilizaliturri, F; Zinzani, PL; Seymour, JF; Balbas, M; Nair, B; Abada, P; Wang, C; Ruppert, AS; Wang, D; Tsai, DE; Wierda, WG; Jurczak, W;
Details: Publication Year 2023-07-06,Volume 389,Issue #1,Page 33-44
Journal Title: New England Journal of Medicine
Publication Type: Research article
Abstract: BACKGROUND: Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have poor outcomes after the failure of covalent Bruton's tyrosine kinase (BTK) inhibitor treatment, and new therapeutic options are needed. Pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor, was designed to reestablish BTK inhibition. METHODS: We conducted a phase 1-2 trial in which patients with relapsed or refractory B-cell cancers received pirtobrutinib. Here, we report efficacy results among patients with CLL or SLL who had previously received a BTK inhibitor as well as safety results among all the patients with CLL or SLL. The primary end point was an overall response (partial response or better) as assessed by independent review. Secondary end points included progression-free survival and safety. RESULTS: A total of 317 patients with CLL or SLL received pirtobrutinib, including 247 who had previously received a BTK inhibitor. Among these 247 patients, the median number of previous lines of therapy was 3 (range, 1 to 11), and 100 patients (40.5%) had also received a B-cell lymphoma 2 (BCL2) inhibitor such as venetoclax. The percentage of patients with an overall response to pirtobrutinib was 73.3% (95% confidence interval [CI], 67.3 to 78.7), and the percentage was 82.2% (95% CI, 76.8 to 86.7) when partial response with lymphocytosis was included. The median progression-free survival was 19.6 months (95% CI, 16.9 to 22.1). Among all 317 patients with CLL or SLL who received pirtobrutinib, the most common adverse events were infections (in 71.0%), bleeding (in 42.6%), and neutropenia (in 32.5%). At a median duration of treatment of 16.5 months (range, 0.2 to 39.9), some adverse events that are typically associated with BTK inhibitors occurred relatively infrequently, including hypertension (in 14.2% of patients), atrial fibrillation or flutter (in 3.8%), and major hemorrhage (in 2.2%). Only 9 of 317 patients (2.8%) discontinued pirtobrutinib owing to a treatment-related adverse event. CONCLUSIONS: In this trial, pirtobrutinib showed efficacy in patients with heavily pretreated CLL or SLL who had received a covalent BTK inhibitor. The most common adverse events were infections, bleeding, and neutropenia. (Funded by Loxo Oncology; BRUIN ClinicalTrials.gov number, NCT03740529.).
Publisher: Massachusetts Medical Society
Keywords: Humans; *Antineoplastic Agents/adverse effects/therapeutic use; Hemorrhage/chemically induced; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy; Neutropenia/chemically induced; Progression-Free Survival; *Protein Kinase Inhibitors/administration & dosage/adverse effects/therapeutic; use; Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors
Department(s): Clinical Haematology
PubMed ID: 37407001
Publisher's Version: https://doi.org/10.1056/NEJMoa2300696
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-10-24 12:17:00

Last Modified: 2024-07-09 06:26:11